Experimental Study Shows Link between Cerebrospinal Fluid IL-6 and Depressive Symptoms in Humans

Experimental Study Shows Link between Cerebrospinal Fluid IL-6 and Depressive Symptoms in Humans

A recent study published in Molecular Psychiatry suggests that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration.

Inflammation is a physiological response to infection and tissue injury that involves the release of pro-inflammatory (e.g., TNF-α, IL-6) and anti-inflammatory (e.g., IL-10) cytokines from activated immune cells. The primary function of these mediators is to coordinate local and systemic immune responses. However, the actions of cytokines are not confined to the peripheral immune system.

There is a large body of evidence that these mediators also profoundly affect brain functions, mood and behavior, leading to the hypothesis that inflammatory mechanisms might be involved in the etiology and pathophysiology of neuropsychiatric disorders such as depression.

Experimental findings in animals have provided important insights into the cellular and molecular mechanisms underlying inflammation-induced behavioral changes. However, human emotional states cannot be sufficiently modelled in animals, which calls for translational approaches linking peripheral inflammation and affective symptoms in humans.

One of the most powerful of these approaches is the model of experimental endotoxemia, in which acute systemic inflammation is elicited by the administration of purified bacterial endotoxin (lipopolysaccharide, LPS). LPS is a prototypical pathogen-associated molecular pattern that activates the innate immune system through a Toll-like receptor 4-dependent pathway.

Studies in healthy volunteers have shown that intravenous injection of endotoxin rapidly leads to dose-dependent increases of cytokine concentrations in the circulation, which are accompanied by changes in brain neural activity and affective symptoms such as negative mood, anhedonia, and social disconnection. It remained unclear however, how the inflammatory message is transported from the periphery to the brain and whether and which cytokines are involved in this communication process.

In the Molecular Psychiatry study, Harald Engler and Manfred Schedlowski from the Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Germany, demonstrated that IL-6 might be one of the key messengers transferring the inflammatory signal from the periphery to the brain. They show in healthy male volunteers that intravenous administration of low-dose endotoxin (0.8 ng/kg body weight), not only induced a significant rise in peripheral blood cytokine concentrations (TNF-α, IL-6, IL-10) but also resulted, with some latency, in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF).

Moreover, they observed a strong association between the endotoxin-induced increase of IL-6 in the CSF and the severity of mood impairment, with larger increases in CSF IL-6 concentration followed by a greater deterioration in mood.

These findings suggest that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration, identifying IL-6 as a potential therapeutic target in mood disorders.

Source: Mol Psychiatry, 2017 Jan 31. doi: 10.1038/mp.2016.264. [Epub ahead of print]
Read more: Molecular Psychiatry

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